Previously supported work provides a heretofore unprecedented demonstration that the transition state for amino acid activation by B. stearothermophilus tryptophanyl-tRNA synthetase (TrpRS) coincides with a significant domain motion that relocates the pyrophosphate binding subsite relative to the adenosine subsite, without changing the tryptophan-binding subsite. Moreover, the domain motion restores significant side-chain packing relationships which are disrupted in and destabilize the pre-transition state TrpRS conformation. Thus the active site does provide a static mould for the transition-state configuration as it does in commonly accepted models of enzymic catalysis. Rather, protein conformation may itself play an unprecedented, and more active role. TrpRS is thus an excellent model for investigating how catalysis can be linked to protein conformation. [unreadable] [unreadable] The most obvious gaps in the structure reaction profile include the structures of the transition state itself and tRNA complexes involved in acyl-transfer and product release, for which crystals are now available to be solved. A key puzzle is the structure of adenine nucleotide in the transition state, which is accessible via proposed kinetic isotope measurements. Finally, the structural data now in hand, together with the proposed new structures establish compelling analogies exist between important intramolecular interactions during TrpRS catalysis and allosteric behavior in oligomeric proteins. These justify a detailed investigation of the thermodynamic relationships that link the binding of different ligands to specific protein conformational transitions, and how they function in catalysis. We propose further to assess these relationships by thermodynamic measurements (calorimetry) and theoretical studies (molecular dynamics simulations) to provide an extensive, overlapping set of equilibrium constants and enthalpies from which an integrated account of thermodynamic linkage relationships can be developed. [unreadable] [unreadable] The enzymatic cycle involves at least three distinct TrpRS conformations - open, closed, pre-transition state, and products - which are homologous to similar sets of three conformations observed in energy transducing ATPases like myosin and F1 ATPase. Ground-state destabilization in TrpRS likely has close analogies with similar phenomena in such enzymes.